Approximately half of AIDS related lymphomas are associated with infection by gamma herpesviruses. Most commonly, Epstein-Barr virus (EBV) is found in the lymphoma cells. A small proportion of AIDS-related lymphomas (approximately 5%) contain the Kaposi's sarcoma herpesvirus (KSHV), frequently in addition to EBV. KSHV-positive lymphomas usually present as primary effusion lymphomas (PEL), although solid variants exist. While rare, PELs have been very useful to study the role of KSHV in malignancies. Study of survival signals in PEL has led us to the identification of the transcription factor NF-kB as a critical signaling pathway, and of vFLIP as the gene encoded by KSHV that elicits NF-kB activation in latently infected PEL cells. vFLIP signaling to NF-kB is necessary for tumor cell survival. With respect to the more common EBV-associated lymphomas, NF-kB is also a critical cellular survival signal;the EBV-encoded proteins LMP1 and LMP2A are the critical viral survival signals in some of these tumors. Our broad hypothesis is that viral proteins provide survival signals, and that interference with these signals can be used as a pathogen-specific therapeutic approach for viral malignancies. Our goal is to better understand EBV-associated lymphomas by performing a comprehensive analysis to dissect the viral signals that are critical for tumor cell survival, in order to use a rational combinatorial approach for the treatment of AIDS lymphomas. This will be done through the following specific aims: 1) Characterize the mechanistic basis for the critical role of LMP2A in the setting of EBV-related lymphomas;2) Evaluate EBV gene and microRNA expression in EBV+ AIDS-related lymphomas;3) Determine which EBV-encoded gene products provide survival signals in EBV-associated lymphomas. This work will reveal which viral gene products are involved in EBV lymphomagenesis and will help select viral targets for selection of appropriate owth of lymphoma cells. Our data will help elucidate how best to inhibit EBV to improve the treatment of AIDS patients with lymphoma.